The goal of this project is to characterize the biochemical events underlying nerve cell degeneration during aging. Specific attention focuses upon two mechanisms, which may be related. Primary emphasis is directed towards calcium-activated proteases (calpain) which can degrade cytoskeletal structures. Calpain activity and levels will be assayed in different brain regions of numerous animal species using enzymatic assay procedures and antibody binding techniques; the data will then be compared to cell degeneration in the particular areas and to the expected lifespan of the species. Calpain's role in the aging process will then be inferred from these results. In related studies, the activity of lysosomal proteases will also be assayed. Further experiments are designed to examine the distribution and the physiological consequence of lipofuscin or lipofuscin-like dence-body accumulations in the brain. Using morphometric methods, the extent of dense-body accumulation will be related to cell loss, calpain levels, and lysosomal protease activities. In addition, electrophysiological parameters, such as membrane potential and resistance, evoked e.p.s.p. amplitudes, and so forth will be examined in hippocampal neurons containing pharmacologically induced dense-body accumulations. Causal relationships between these various phenomena may be deduced for the collected results.